LAUSR

Encoding of memories, including those associated with prior drug or reward, is thought to take place within distinct populations of neurons, termed ensembles. Neuronal ensembles for drug‐ and reward‐seeking have been identified in regions of the medial prefrontal cortex, but much of our understanding of these ensembles is based on experiments that take place in a single reward‐associated environment and measure ensemble encoding over short durations of time. In contrast, reward seeking behavior is evident across different reward‐associated environments and persists over time. Using TetTag mice and Fos immunohistochemistry, we examined the relationship between persistent sucrose‐seeking and ensemble encoding in mice that undergo seeking sessions in the same or different sucrose self‐administration contexts 2 weeks apart. We found that prelimbic (PrL) and anterior cingulate cortex ensembles tagged in the first seeking session were highly sensitive to the context in which a second seeking session took place: reactivation of these ensembles was reduced in the same context but elevated in a distinct sucrose self‐administration context. Correlational analyses revealed that ensemble reactivation in the PrL was proportional to the persistence of sucrose seeking behavior across sessions in differing ways in female mice. In the same context, reactivation was proportional to the persistence of non‐reinforced operant responses, whereas in a distinct context, reactivation was proportional to the persistence of non‐reinforced head entries into the sucrose receptacle. This study underlines the importance of the medial prefrontal cortex importance in maintaining a reward‐seeking ensemble over time and identifies context‐dependent changes in behavioral correlates of ensemble reactivation.